Immunization with Cocktail of HIV-Derived Peptides in Montanide ISA-51 Is Immunogenic, but Causes Sterile Abscesses and Unacceptable Reactogenicity

BACKGROUND: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA). METHODS: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens. RESULTS: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions. CONCLUSIONS: The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000886

Risk behaviour and time as covariates for effi cacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144

Background The Thai phase 3 HIV vaccine trial RV 144 showed modest effi cacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine effi cacy. We did a post-hoc analysis of the trial’s data to investigate behavioural risk and effi cacy every 6 months after vaccination. Methods RV 144 was a randomised, multicentre, double-blind, placebo-controlled effi cacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18–30 years were recruited from the community. In this post-hoc analysis of the modifi ed intention-to-treat population (16 395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classifi ed participants’ behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal eff ects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Findings Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classifi ed as high or increasing risk at least once during followup were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition effi cacy was signifi cant (p=0·01), with greater benefi t in low-risk individuals. Vaccine effi cacy seemed to peak early—cumulative vaccine effi cacy was estimated to be 60·5% (95% CI 22–80) through the 12 months after initial vaccination—and declined quickly. Vaccination did not seem to aff ect viral load in either early or late infections. Interpretation Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment eff ects. The regimen tested in the RV 144 phase 3 trial might benefi t from extended immunisation schedules. Funding US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health